ABSTRACT Concern about neurotoxicity following exposure to surgery and anesthesia in childhood has persisted for nearly two decades, in part because there is no conclusive evidence to prove that it exists, nor is there adequate evidence to prove that it does not. Large-scale observational studies evaluating neurobehavioral outcomes after exposures to anesthesia and surgery have generated variable results, but none have demonstrated actionable, un-confounded evidence suggesting increased risk. This proposal seeks to better define the association between exposure to anesthesia and surgery and subsequent neurobehavioral disorders (defined as behavioral disruptive disorders, mood disorders, and anxiety disorders) through a new analysis of existing Medicaid data that has the potential to overcome limitations of previous studies. This study uses a new approach for examining the question by: (1) using a natural experiment that reflects a stochastic exposure to surgery (the near random event of appendectomy after controlling for age, sex and race) that is not associated with lifestyle or disease-related treatments that may themselves be associated with long-term neurobehavioral outcomes, and (2) through the use of multivariate matching techniques to account for potential observable baseline differences in cohorts, we have the ability to compare an exposed cohort of approximately 68,000 pediatric appendectomy patients with 340,000 matched controls that are closely balanced for both observable and potentially unobservable risk factors. This enables us to better study if there is a long-term association between operative exposure with general anesthesia and subsequent adverse neurobehavioral outcomes in children. Finally, (3) we will also examine a 68,000-patient medical control group with acute medical conditions such as gastroenteritis, cellulitis and, community-acquired pneumonia to examine if neurobehavioral disorders are elevated in this group not exposed to surgery or anesthesia. The study will examine outcomes of ADHD, conduct disorders, anxiety, depression and bipolar disorder, to conduct a multivariate matched cohort study to compare the hazard of study outcomes between exposed and unexposed children in Medicaid. We hypothesize that patients with appendectomy will have an elevated hazard of these study outcomes as compared to controls. We will identify all patients who underwent appendectomy from ages 3 to 15 years, and match each patient to 5 controls who were the same age, omitting any exposed or control patient with a baseline history of neurobehavioral disorders in the primary analysis or with evidence of complex chronic disease, and perform a second 1:1 match between the appendectomy treated group and children who were admitted for acute medical conditions. The results of this study will be generalizable beyond appendectomy precisely because appendicitis occurs randomly (after matching on age, sex, and race) and should aid in informing caregivers about potential neurobehavioral risks associated with general anesthesia and surgery.